Abstract

BACKGROUND: Tumor progression within a brain is the process of acquiring malignant genetic mutations from glial progenitor cells, dodging their original developmental fate and deteriorating functional connectivity of CNS. In order to devise effective targeted therapeutic strategies, understanding distinct molecular and phenotypic evolutionary features of cancer clones is eminent.

RESULTS: We found evidence of branched evolutionary patterns within and across two histopathological separated tumor regions. Both tumors have high clonal probable somatic mutations, and evolutionary inference showed clonal lineage between two tumor regions was divided at early time during tumor progression. For all patients, the gene expression signatures within a tumor were heterogeneous but converged towards mesenchymal phenotype in the aggressive region. In the first case, the left tumor was self-limiting and showed mixed proneural and classical gene expression signatures whereas the right side tumor has expanded to the corpus callosum with EGFR overexpression and mesenchymal gene expression. In a case of a monocentric tumor with PDGFRA amplification, cancer cells disseminated from the core mass with massive immune cell infiltration underwent transcriptome switching from proneural to mesenchymal gene expression, with a concomitant FGFR1 copy number gain and mutation. Lastly, in a secondary glioblastoma with IDH1 mutation, GLIOLAN positive glioblastoma was surrounded by grade III oligodendroglioma. The two tumor areas showed intermingled heterogeneous gene expression signatures, with upregulation of astrocytic/mesenchymal genes in the GLIOLAN positive tumor cells.